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Molecule may extend drug life in the body

Designer molecules aim to fine-tune enzyme activities

An unassuming molecule called benzil has given rise to a potentially exciting family of compounds that could play an important role in extending the life of therapeutic drugs in the body, according to St. Jude researchers. The benzil-based family of compounds inhibits enzymes called carboxylesterases (CEs) found in the lung, liver, kidney, intestines and other organs.

CEs metabolize a host of compounds, including toxins such as heroin and cocaine, as well as the clinically used drugs CPT-11, capecitabine, Demerol and flestolol. The researchers used biochemical and computer graphics techniques to design benzil-based molecules that inhibit specific CE enzymes. The goal of the work is to develop CE inhibitors that have specific therapeutic effects, according to Phil Potter, PhD, Molecular Pharmacology. Potter is senior author of a report on this work that appears in the current online edition of Journal of Medicinal Chemistry.

The exact function of CEs is unclear. They can be highly beneficial in preventing drug overdoses. But they also prematurely deactivate medical drugs, such as those needed to control blood pressure, Potter said. This happens in the case of flestolol, a drug that is typically used to treat angina, hypertension, arrhythmia and migraine.

“This drug’s usefulness has been almost totally compromised because CEs break down flestolol too quickly for it to have a long-lasting effect,” Potter said. “If we could selectively inhibit the CE responsible for flestolol metabolism, the half-life of the drug would be greatly increased, allowing more time for it to have an effect.”

The development of designer-CE inhibitors by St. Jude is particularly noteworthy because, unlike other CE inhibitors produced by other researchers, the benzil-based inhibitors are non-toxic, Potter said. “Our inhibitors do not disrupt neurotransmitters—the chemicals nerves use to communicate with each other,” he said. “This suggests that they can be used to develop potentially safe drugs for use in humans.”

The St. Jude team collaborated with researchers from the University of Mississippi and Telik Inc., a biopharmaceutical company.